This Breast Cancer SPORE Project focuses on a new strategy: to turn the action of an active telomerase against the breast cancer cells. In the course of the previous funding cycle, we have successfully demonstrated that a low threshold of expression of mutant-template telomerase RNA (MT-hTer) genes in human breast cancer cells is sufficient for a potent killing and growth inhibitory effect on these cells. This answers the main question we had sought to address: can teloemrase be a molecular target for anti-cancer therapy. For the new five-year funding period the goal of the project is therefore the exploitation of these novel, surprisingly potent and dominant effects, which are based on "toxic" telomeres, as a potential anti-cancer therapeutic strategy: The specific aims for the next 5 years are: Aim 1: Test the effects of delivering MT-hTer genes by receptor (HER2)-targeted immunoliposomes to HER2- overexpressing human breast cancer cells. Test cells a) in culture, b) grown as tumors in the nude mouse xenograft system. Using the same delivery and nude mouse xenograft system, test the effects on tumor growth of delivering telomerase RNA-specific oligonucleotides, designed to induce MT-hTer-mimetic effects ("AbTel" oligonucleotides). Aim 2: Test MT-hTers for the ability to prevent the growth of breast epithelial tumor cells taken directly from surgically removed human tumors or collected by ductal lavage. Similarly, test any "AbTel" oligonucleotides identified in Specific Aim #1. Determine whether individual cancers with different genetic properties differ with respect to the "toxic telomerase" effects, with the goal of eventual tailoring of therapy to individual tumors. Aim 3: Determine which MT-hTer mutants and which gene delivery vectors have the most potent effects on cell growth and apoptosis rates. Aim 4: Determine whether combining MT-hTer with a) anti-wild type telomerase RNA ribozyme, b) small interfering RNA directed against WT-hTER or telomerase hTERT mRNA, or c) anti-sense nucleic acids, increases the potency of the MT-hTer effects on cell growth and apoptosis rates.